The unrelenting obesity epidemic has led to a dramatic increase in the incidence of type 2 diabetes and its associated microvascular and macrovascular complications. Minorities - African Americans, and Mexican Americans are affected disproportionately by type 2 diabetes, but the reasons are incompletely understood. Like Zucker Diabetic Fatty (ZDF) rat model, human type 2 diabetes is characterized by progressive inability of pancreatic islet beta cell to compensate for tissue insulin demands due to insulin resistance. In ZDF rats, a major mechanism of progressive islet beta cell failure is excessive accumulation of triglyceride in the pancreas, leading to production of toxic intermediates that cause beta cell apoptosis. In ZDF rat model, the beta cell failure can be prevented by the treatment with thiazolidinedione agents. We recently have had a major technological breakthrough in which 1H MRS allows precise measurement of pancreatic triglyceride content in humans. Having now validated the technique in ZDF rat model and human subjects, our new human pilot data lead us to hypothesize that profound ethnic differences in a regional fat distribution are such that pancreatic steatosis plays much more important role in the pathogenesis of beta cell failure and type 2 diabetes in Mexican Americans than in African Americans. Such striking ethnic differences should provide new insights into mechanisms and therapeutic targets for preserving beta cell function in high risk human populations. We hypothesize that pancreatic steatosis constitutes a major mechanism leading to beta cell failure in persons with an inadequate subcutaneous fat storage pool. We further hypothesize that regression of pancreatic steatosis is an important mechanism by which thiazolidinedione rescue beta cell function in human diabetes. Our specific aims are as follows: Aim 1: Understanding ethnic differences in the mechanisms underlying beta cell failure in Mexican Americans, African Americans and Whites; Aim 2: Reversing pancreatic steatosis and protecting 2 cell function with pioglitazone treatment in Mexican Americans, and African Americans. To achieve our aims we will study 210 individuals in Aim 1 and 80 in Aim 2. We will use MRS to measure levels of fat within pancreas, MRI to measure fat mass, and frequently sampled iv glucose tolerance test (FSivGTT) to access beta cell function. PUBLIC HEALTH RELEVANCE: Although obesity is a major risk factor for diabetes, many obese individuals never become diabetic. Furthermore, type 2 diabetes certainly can develop in lean persons. We hypothesize, that pancreatic steatosis constitutes a major mechanism leading to beta cell failure and that regression of pancreatic steatosis is an important mechanism by which thiazolidinedione rescue beta cell function in human diabetes. If we confirm this hypothesis, pancreatic TG content could be used to enhance diabetes risk prediction and to identify individuals who would benefit from early targeted interventions to prevent type 2 diabetes. With further technological refinements regarding the ease of the pancreatic TG levels measurement, pancreatic MRS could become broadly applied clinical diagnostic tool.